RTEF-1 variants and uses thereof

Abstract

Disclosed are variant RTEF-1 polypeptides having an RTEF-1 amino acid sequence with one or more internal deletions, wherein the polypeptides reduce VEGF promoter activity. Some of the RTEF-1 polypeptides include an amino acid sequence that is at least 80% identical to the contiguous amino acids of 1) amino acids 24 to 47 of SEQ ID NO:15 and 2) each of SEQ ID NOs:16 and 17, but does not comprise the contiguous amino acids of SEQ ID NOs:8, 9, 11, or 12. Also disclosed are nucleic acids encoding the variant RTEF-1 polypeptides of the present invention. Pharmaceutical compositions that include the polypeptides and nucleic acids of the present invention are also disclosed. Methods of inducing cell contact inhibition, regulating organ size, and reducing intracellular YAP activity are also set forth, as well as methods of treating hyperproliferative diseases such as cancer using the pharmaceutical compositions of the present invention.

Description

[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 325,675 filed Apr. 19, 2010, which is incorporated herein by reference in its entirety.[0002]The invention was made with government support under Grant No. NEI / NIH 1R01EY019042-01A1 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]1. Field of the Invention[0004]The invention concerns the fields of molecular biology, cell biology, clinical medicine, pharmacotherapy, and oncology.[0005]2. Description of Related Art[0006]Transcriptional enhancer factor 1-related (RTEF-1) gene is a member of the TEA DNA binding domain gene family. The TEA DNA binding domain gene family is highly conserved from Aspergillus nidulans, yeast, Drosophila, mice to human. The TEA DNA binding family of proteins can be involved in both activation and repression of different genes and their particular function can be modified by association with other pr...

AI Technical Summary

Benefits of technology

[0013]The present invention is in part based on the identification of splice variants of RTEF-1 that are particularly effective at reducing VEGF production. The enhancer isoforms (447 and 1305) are believed to be capable of binding the VEGF promoter to regulate gene expression whereas the inhibitor isoforms (651, ss651RMR, 366 and 669 and modifications of these isoforms), that usually lack a nuclear localization signal, repress VEGF production at the cellular level resulting in lower levels of secreted VEGF165.

[0014]Given the prominent role of VEGF in a wide variety of diseases, such as cancer and other diseases associated with vascular proliferation, these RTEF-1 variants represent a new subset of therapeutic agents. The RTEF-1 variants of the present invention are also believed to be effective in reducing YAP activity in cells that overexpress or have elected YAP activity, such as certain cancer cells. The RTEF-1 variants of the present invention can thus be applied in regulating the amount of active YAP in the cytoplasm or nucleus of target cells, thus regulating cell growth and proliferation.

Problems solved by technology

Disruption can lead to excessive tissue loss with subsequence loss of function as in the case of excessive apoptosis or uncontrolled cell proliferation.

Once dysregulated, it can lead to a malignant phenotype.

Malignant cells might produce excess YAP during genomic amplification that might overwhelm the normal physiologic regulatory systems and result in abnormal cytoplasmic accumulation.

The stability of YAP may be altered in neoplastic tissues resulting in ineffective protein turnover and excessive YAP activity.

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